Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, UK.
Department of Neuroscience, Erasmus Medical centre, Rotterdam, The Netherlands.
Abstract
Schizophrenia is a heterogeneous disease characterised by an array of clinical manifestations. A large number of studies over the last 20 years have pointed towards
immune system abnormalities in patients suffering from this condition. In addition, the psychosis and cognitive dysfunction associated with schizophrenia have
been shown to be linked with autoimmune diseases. Here, we review the evidence, which suggests that a pro-inflammatory status of the immune system induces
psychopathologic symptoms and may be involved in the pathophysiology of this major mental illness. We also propose that future preclinical and clinical stu
dies should take such pre-defined causes and the dynamic status of the inflammatory component into account. Patient stratification and personalised medicine
strategies based on targeting the inflammatory component of the disease could help in alleviation of symptoms and slowing disease progression. Ultimately, this
could also lead to novel concepts in schizophrenia target/molecular identification and drug discovery strategies.
Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34
Keywords: Schizophrenia, inflammation, immune system, biomarkers.
Resumo
A esquizofrenia uma doena heterognea caracterizada por um conjunto de manifestaes clnicas. Um grande nmero de estudos ao longo dos ltimos 20 anos
apontou para anormalidades no sistema imune em pacientes que sofrem dessa condio. Em adio, tem sido mostrado que a psicose e a disfuno cognitiva
associadas com a esquizofrenia esto ligadas a doenas autoimunes. Aqui, revisamos a evidncia que sugere que um status pr-inflamatrio do sistema imune
induz sintomas psicopatolgicos e pode estar envolvido na fisiopatologia dessa principal doena mental. Tambm propomos que futuros estudos pr-clnicos e
clnicos deveriam levar em conta tais causas predefinidas e o status do componente inflamatrio. Estratificao de pacientes e estratgias de medicina personali
zadas baseadas no direcionamento ao componente inflamatrio da doena poderiam ajudar na reduo de sintomas e da progresso da doena. Por fim, isso
poderia levar a novos conceitos na identificao de alvos moleculares em esquizofrenia e estratgias de descoberta de drogas.
Rahmoune H, et al. / Rev Psiq Cln. 2013;40(1):28-34
Palavras-chave: Esquizofrenia, inflamao, sistema imune, biomarcadores.
Introduction
Schizophrenia is a complex psychiatric disorder which affects approximately 1% of the world population. Although considerable progress
has been made in the search for contributing factors, the aetiology
of the disease is still far from understood. Heterogeneity throughout
the onset and progression of schizophrenia is a major factor slowing
down scientific progress in the field. Another complicating factor is
the overlap of symptoms with other psychiatric and neurological
disorders and it remains unclear whether the different manifestations reflect subtypes with different aetiologies or whether diverse
clinical syndromes may have overlapping pathologies. These factors
have led to a high rate of misdiagnosis using the current subjective
clinical rating systems1. For this reason, there is now intensive effort
to identify more empirical measures based on molecular fingerprints
underpinning the disease aetiology. One problem is the need to
identify peripheral biomarkers which can be measured easily in the
clinic. Previously the main focus of schizophrenia research has been
to identify pathophysiological changes in the brain, a biomaterial
which is largely unavailable to the clinician for diagnostic purposes.
Thus aspects of the disorder that are reflected in peripheral tissues
are an important focus for biomarker discovery.
Here, we review the advances made in elucidating the potential
role of the immunological component of schizophrenia. There has
been considerable evidence indicating the significance of neuroin-
Address correspondence to: Hassan Rahmoune. University of Cambridge, Tennis Court Road, Cambridge. CB2 1QT, UK. Telephone: +44 1223 334 151 Fax: +44 1223 334 162. E-mail: hr288@cam.ac.uk
Brain studies
The pro-inflammatory status associated with neuropsychiatric diseases has been extensively investigated and well established11.The
activation of the brain immune system has been suggested by the
increased levels of IL-1 in the cerebrospinal fluid in first-episode
schizophrenia patients12. Brain development is also known to be
regulated by pro-inflammatory agents13,14. Maternal infection in
pregnancy can increase the risk of developing schizophrenia by impacting the neuro-developmental stage in the foetus. This is due to
the fact that the balance between pro and anti-inflammatory agents
may influence brain development and behaviour15.
Transcriptomic profiling of post-mortem brain or peripheral
tissues can provide useful insights into the perturbed biological
processes in central nervous system disorders. The gene expression
level of pro-inflammatory cytokines in preclinical models of schizophrenia and human subjects have been shown to be increased in the
prefrontal cortex region of the brain16. Several transcriptomic studies
have shown that inflammation-related genes which are increased
in schizophrenia brains are also associated with oligodendrocyte
and endothelial cells. In these cells, transcription can be induced by
the inflammatory cytokines tumour necrosis factor alpha (TNF-),
interferon alpha (IFN-) and interferon gamma (IFN)-17-19. Ho
wever, these effects are likely to be confounded by antipsychotic
drug-treatment, poor diet or unhealthy life styles, which are often
associated with chronic stages of the disease15.
The availability of tissues which are more accessible is necessary
to apply these approaches clinically. A recent study carried out data
analysis from the transcriptomic profiling of 33,698 genes in 79
human tissues20. The results suggested that while whole blood cells
share significant gene expression similarities with central nervous
system tissues, the correlation between transcripts present in both
of these was around 0.5, which was less than immune tissues (0.64)
and comparable to a somatic tissues (0.57). The authors concluded
that gene expression in whole blood cells is only partially correlated
with that seen in brain tissues.
There are also numerous reports of immune abnormalities in
the central nervous system and in the periphery of patients with
schizophrenia21-23. Cytokine levels have been measured in brain and
body fluids such as cerebrospinal fluid (CSF) and blood serum of
patients with schizophrenia and a decreased inflammation response
has been linked with decreased production of T helper (Th)-1 cytokines24. The pituitary gland is known to be involved in regulation
of the central nervous system and peripheral tissues by release of
hormones involved in vital body functions. Thus, the pituitary provides a regulatory link between the blood and brain. Furthermore,
the pituitary is controlled by inflammatory stimuli, as the production
of adrenocorticotrophic hormone (ACTH), growth hormone (GH)
and thyroid stimulating hormone (TSH) appears to be regulated by
IL-625. One of the first direct evidence reflecting a pro-inflammatory
status in the brain at the disease onset was provided by Van Berckel
et al.26. Using PET imaging techniques Van Berckel et al. have shown
microglial activation in the brain of schizophrenic patients within the
first five years of the disease onset. Further pre and clinical studies are
needed to unravel the causality of blood and brain pro-inflammatory
status in neuropsychiatric diseases such as schizophrenia. Nevertheless, in the past decades scientists has stipulated that infectious agents
(e.g. herpes simplex virus, Epstein-Barr virus and toxoplasma) as a
possible cause of schizophrenia27 and such a phenomenon may be
explained by chronic infections or compromised immune status.
Finally, a large set of data have also stipulated that environmental
factors such as oxidative stress plays a major role causing or exaggerating the inflammatory component of schizophrenia28.
Peripheral studies
Inflammation has been associated with schizophrenia for decades
and studies of changes in inflammatory molecules may lead to a
means of patient stratification prior to antipsychotic treatment29.
29
A previous study which carried out a meta-analysis revealed alterations in cytokines in blood and cerebrospinal fluid from patients
with schizophrenia30. Numerous studies have reported that circulatory and cellular pro-inflammatory alterations are associated with
schizophrenia31. Analysis of the transcriptome pattern in circulating
monocytes isolated from patients suffering from schizophrenia and
bipolar disorder showed a pro-inflammatory status associated with
monocyte and T-cell activations32. However, some of these studies
have provided an inconsistent picture, which is most likely due to
differences in the number or type of cytokines measured33,34 or the
presence of confounding factors such as different disease subtypes,
co-morbidities, illness duration and the fact that patients had been
treated with antipsychotics. In addition, many of these studies have
been performed using peripheral blood mononuclear cells (PBMC)
which may have led to inconsistencies related to differences in the
isolation procedures used. The macrophage-T cell theory of depression and schizophrenia35 postulates an aberrant inflammatory
state of monocytes, macrophages and T cells in patients with mood
disorders or schizophrenia is contributing to the illness. Aberrant
levels of inflammatory cytokines can destabilize function of the brain
and the hypothalamic-pituitary-adrenal (HPA) axis, which can lead
to changes in mood and behaviour. Most studies have focused on
serum levels of neopterine or other cytokines in targeted approaches
and these demonstrated the presence of an aberrant inflammatory
state in psychiatric patients. However, this has led to inconsistent
results as single determinations are not precise or robust enough to
consistently measure alterations in immune function.
In a study aimed at identifying proteomic signatures and molecular pathways underlying schizophrenia, we carried out multiplex
immunoassay analyses of serum samples from first-episode, drug
naive schizophrenia patients which resulted in identification of
a disease signature36. Interestingly, many of these molecules have
been implicated previously in patients with auto-immune37,38 or
metabolic diseases39. Further study of these pathways may result in
important breakthroughs in schizophrenia research as this could
lead to a means of stratifying patients prior to treatment. It could
also lead to the development of new supplemental therapies which
target the inflammatory aspects of the disease. Recent studies have
explored the possibility of using immuno-modulatory drugs such as
cyclooxygenase-2 (COX-2) inhibitors and these have been reported
to have beneficial effects on schizophrenia symptoms40,41. In addition, anti-diabetic compounds such insulin-sensitizing agents have
already been used in targeting the cognitive deficits in Alzheimers
disease patients and could equally be tested for improvement of
similar symptoms in schizophrenia42.
30
Clinical need
There is now agreement that there is a fundamental lack of understanding of the biological abnormalities associated with severe mental
illnesses, which are still defined by vague symptomatic descriptions
that do not address the etiological heterogeneity of these conditions.
The available therapeutic regimes are aimed largely at relieving
symptoms and may only slow or halt disease progression at an early
stage. Thus early and accurate diagnosis is essential.
Many patients with neuropsychiatric diseases such as schizophrenia remain unrecognised or have received incorrect or late diagnoses.
The recognition rate of schizophrenia in primary care settings is less
than 50%. The main reason for this is that the current diagnosis of
schizophrenia is subjective. This is a result of the complex spectrum of
symptoms, the overlap of these symptoms with those in other mental
disorders, and the current lack of empirical markers specific for these
diseases. Moreover, less than 50% of schizophrenia patients respond
favourably to an initial treatment with antipsychotic medication86,87.
This is most likely a result of the insufficient understanding of the
underlying pathophysiology of schizophrenia to inform diagnosis or
guide treatment selection. Furthermore, traditional pharmacotherapy
for schizophrenia using blockbuster drugs usually leads to admi
nistration and switching of drugs multiple times until an adequate
response is achieved. It is perhaps not surprising that there is a low
treatment response rate and that relapse is common88.
The idea of personalized medicine approaches in psychiatric
could be realized using molecular biomarkers which target subgroups
of patients based on inflammatory, metabolic or HPA axis status. A
molecular test that recognizes such subtypes may also be used for
identifying those patients who are most likely to respond to a particular treatment89. The development of empirical immuno- or neuroendocrine markers and objective diagnostic and prognostic blood tests
for psychiatric disorders, based on an integral approach of proteomics
would be a major breakthrough in the field of schizophrenia. The discovery of novel diagnostic or therapeutically useful biomarkers involves
profiling of biological samples in search for disease related qualitative
and quantitative changes of molecules. Biomarkers which target alterations in the immune system, for example, could form the basis of novel
empirical tests for patient stratification at the onset and throughout
disease progression. This will ultimately pave the way for personalised
medicine strategies with a focus on the inflammatory component of
the disease. Nevertheless, environmental effects (seasonal illnesses)
and co-morbidities (diabetes, metabolic syndrome) associated with
schizophrenia should be considered when these strategies are applied.
Most of the omic studies conducted on peripheral and central
systems document only an association between pro-inflammatory
status and schizophrenia, and not a cause or effect. We have successfully used molecular profiling platforms to identify specific schizophrenia brain and serum signatures relating to immune function/
31
Conclusion
It is has been established that central and peripheral pro-inflammatory status is a significant component of schizophrenia. As ongoing
32
Genetic pre-disposition
Neuro-developmental defect
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Schizophrenia
inflammatory component
17.
Aid diagnostic
Blood/brain molecular
stratification
(Omics and clinical rating)
18.
Novel therapy
Adjuvant therapy
Anti-inflammatory
modulators
19.
20.
21.
22.
Acknowledgments
This research was supported by the Stanley Medical Research Institute
(SMRI), the European Union FP7 SchizDX research programme
(grant reference 223427) and the NEWMEDS Innovative Medicines
Initiative.
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